Inspiration, Not Imitation

Ben Xinzi Zhang

Human aviation started with the imitation of birds. At first, the image of flapping wings was so integral to our idea of flying that it seemed only foolish to dismiss nature’s design. Yet today, we fly in aircrafts with jet engines and propellers. Although airplanes have wings, the structural inspiration that engineers drew from birds only took us so far. As land-bound animals, humans need a lot more thrust and lift than a pigeon.

What allows us to move beyond skin-deep mimics is science. Through detailed studies of the laws of nature, we distill natural functions into physical relationships and design on an abstract level. To address our need for sustainable and efficient energy, scientists at Energy Frontier Research Centers (EFRCs) turn inspirations from nature into practical solutions.

Functions first

At the Center for Molecular Electrocatalysis (CME), chemists Wendy Shaw and Aaron Appel find themselves learning tropes of chemistry from nature as they try to store solar electricity for a cloudy day.

The “bird” that they aim to re-create was found in an unassuming cluster of molecules inside a nitrogen-harvesting bacterium more than 80 years ago. Known today as a hydrogenase, it accelerates molecular transformations that seem at most peripheral to its natural host, helping to combine two protons and a pair of electrons to form a stable hydrogen molecule (H2). To a chemist, re-creating this process in a test tube is no less daunting than translating avian anatomy into airplanes.

But how will the remarkable chemistry of the hydrogenase help us store electricity? Here’s the idea. Once a steady flow of electrons is generated from a solar panel and passed through an acidic solution abundant in protons, the catalyst can fuse the protons and electrons, effectively storing the electrical energy inside the stable chemical bonds of H2 molecules. Then, whenever electricity is needed, we simply liberate those electrons from H2, using the same or another catalyst, while the leftover protons stand ready for the next cycle of energy storage. Though inspired by hydrogenase, the scheme cannot be realized by the natural catalyst. Nature simply did not design it with our plan in mind, especially not on a scale that our modern appetite for energy demands.

The job falls on scientists, and their first jab at the challenge was essentially to put on a pair of wings. Pioneers in the field successfully synthesized molecules that closely resembled the shape of the core of hydrogenase. “They typically were not at all functional,” said Appel. “They structurally look similar, but they did not work.”

Proton relay. In hydrogenase-inspired catalysts, protons (red spheres) are efficiently relayed from the solution environment to the metal center (Ni), where electrons are traded to effect chemical change. Chemists often visualize nitrogen and oxygen atoms with electron clouds (blue), which attract the positively charged protons. By artificially installing an amino acid that helps relay the proton, CME functionally re-creates the natural function in the catalyst. Image adapted from Dutta et al.

Daniel DuBois, a founding member of CME, started on a different route. Using a synthetic template that chemists were already familiar with, he looked to hydrogenase for functional inspirations instead. What part of the natural structure has to be mimicked for it to work, and how could it be re-created with known chemistry?

The core function involves the nimble delivery of protons to and from the metal center, where the electrons are traded. DuBois found that by mimicking the arrangement of atoms three bonds away from the hydrogenase metal center, his synthetic analog gained improved functionality. His success inspired Appel and Shaw to look beyond the last leg of the proton relay. It was there that evolution’s ingenuity left them perplexed. “Certainly in the natural system there are many different possible proton pathways,” said Appel. But it would be a nearly impossible task to replicate nature’s precise route.

Shaw was unfazed. She grafted just one layer of amino acids on DuBois’ design and iteratively tuned the structure to carry out each step of hydrogenase’s remarkable feat more efficiently than prior synthetic catalysts. Some modifications assisted the movement of protons, others better synced the trading of electrons. Through continued refinement, her functional mimics were quickly getting faster and more elegant than the painstakingly crafted structural mimics. By shedding the image of a winged human, we move a big step closer to a fully functioning aircraft.

From muscles to hierarchical alignment and back

Scientists rely on abstractions to draw up designs. Here’s an abstract observation. Muscles stretch and contract along one direction, because they are made of numerous little strings. You may call it trivial, but this intuitive explanation is nonetheless a shrewd one, because it is easily turned into a design question—can you replicate the function of a muscle by bundling a whole lot of little strings?

Muscles are made of proteins, which are formidable structures for chemists to reproduce from scratch. Liam Palmer, CBES research director, said, “I just don’t even know where you would begin to design a protein that can do this.”

Their molecules are actually much simpler than a protein. The team introduced the functionality of a muscle using chemical insights and expertise that Samuel Stupp, CBES Director, and his team have gradually mastered over the past two decades.

Here’s their approach. Muscles can expand and contract because the concerted motions of microscopic molecules propagate very well to the macroscopic level. To generate and amplify the concerted motion, you need to bundle many tiny strings.

Artificial muscle. The structure of a muscle features a hierarchical alignment that propagates microscopic actuation to a macroscopic level. The CBES artificial muscle contains bundles of nanofibers with flexible polymer crosslinks that cause the material to shrink in warm water. Top panel adapted from Chin et al. Bottom panel from public domain.

The artificial muscle that Stupp and his CBES collaborators built is essentially a microscopic machine that builds all its well-oiled components on its own. It all started from a kind of nanofiber that the group first reported in 2001. Inspired by the way fragments of natural protein stick together to form large protein clusters, they tailored the structure of these chain-like molecules so that they self-assemble into long fibers. In 2010, CBES senior investigators reported that with special processing, their nanofibers could spontaneously bundle and align themselves into a noodle-like gel. At this point, they were close to making an artificial muscle. If the parallel nanofibers could be linked with a flexible substance that shrinks or expands with the command of an external signal, the gel would contract and stretch altogether.

What helped them make the final leap was another piece of novel chemistry. A student with CBES carefully grew a special class of polymer chains on the bundled nanofibers. In addition to reinforcing the gel, these strands of polymers shrink when immersed in warm water. The fibers now look like a brush with fully planted bristles. When these polymer bristles shrink, the well-aligned nanofibers—the body of the brush—get closer together, causing the gel to contract as a whole. When the water temperature drops, the polymers expand and the gel stretches back.

Palmer described what he saw in muscles as a hierarchically ordered structure, the fractal-like assembly of small chains into fibers, then into bundles and tubes. The artificial muscle perfectly embodies that idea.

To know what birds look like

Airplane engineers certainly know what a bird looks like. Chemists only know their microscopic targets of inspiration—molecules—as drawings that they tinker with in their head. To be able to learn anything meaningful from nature, they often have to go to excruciating lengths to read the impossible font in her manual.

So what is a chemist’s magnifier? It is the rigorous logic of experimental science. Whenever new experimental evidence emerges, we hypothesize a new modification to an existing model and check the new predictions against all available observations. If they match, then we cautiously admit the new modification. If they differ, we make another hypothesis. If enough attempts have been made to save the model, yet there still are unexplained experimental facts, we start building a new model altogether.

Cellulose, the most abundant biomaterial on Earth, is what gives virtually all plants their physical strength and makes everything from paper to clothing. But understanding its structure down to the molecular level proved to be a challenge. The second law of thermodynamics dictates that nature prefers energetically stable structures—arrangements of microscopic particles that are most resilient to energetic disturbances.

Plants often disagree. “There are so many complicating factors when you are dealing with biology, because you can’t really say, ‘we found the lowest energy structure, so it’s the correct one.’ There’s evidence that points towards one, but there are many reasons that a metastable structure might be the one that a plant produces,” said James Kubicki with the Center for Lignocellulose Structure and Formation (CLSF). He is referring to structures that survive minor disturbances but do not typically turn up as the most stable options in state-of-the-art theoretical calculations.

Kubicki was brought into the mix of scientists addressing the challenge through what he described as the genius of Cosgrove’s CLSF organization. “When he originally organized the group, he had about 50% of the people who were familiar with plant cell walls—botanists and biochemists. But the other 50% of us hadn’t worked on that topic at all. We are physical chemists coming into the biology world. [We] came in without having the prejudices and biases that people had from reading the literature from the past thirty years.”

The result? “We challenged many of the fundamental assumptions,” Kubicki said, “and one of those was the size of the cellulose microfibril.”

Many papers had been published on the assumption that there were 36 polymers in the microfibril, the fundamental building block of cellulose in a plant’s cell walls. “That was all based on some microscopy work that looks at this ‘rosette,’ and 36 was a reasonable guess,” said Kubicki.

It was only in the past few years that scientists started to challenge this view. They found that the diameter of a cellulose microfibril couldn’t possibly permit 36 polymer chains. Eighteen became the new understanding.

Not rosettes. The three guesses of the plant cell wall cellulose microfibril structure on Kubicki’s shortlist. They all contain 18 units, arranged in a relatively symmetrical fashion. Image adapted from Kubicki et al.

Just how are these 18 polymers arranged? Kubicki made his reasonable guesses based on previous suggestions in the literature. He then compared theoretical predictions of experimental metrics with observed data, and found a 34443 model to be the most consistent. Vincent Crespi first used the structure in his computational work for the previous phase of the EFRC. When asked how he selected the candidate structures out of the myriad possibilities, Kubicki laughed. “I tend to be an intuitive chemist,” he said. “We were looking for an arrangement that would come up to that 18 but looked like a reasonably symmetric structure.”

Like any good scientist, Kubicki’s creative intuition stopped short of blind confidence. In the conclusion of the 2018 article in which he and his co-authors reported their finding, they stated that the preponderance of evidence suggests that the 34443 habit is the most probable. Why? Because it cannot be eliminated by examining all available data at the time.

While seeking inspiration from nature, chemists are never hindered by the seeming impasse caused by our inability to see molecules. Instead, they constantly produce meaningful advancements by critically combining inventive thinking with abstraction and experimentation.

But to a geoscientist like Kubicki, there is another important key to accessing nature’s treasure trove. “Everything is interacting together [in a system]. So it’s okay to study one thing at a time, but you need to be able to put it together in the end in order to understand the whole system.” Just a wing by itself will surely never fly.

Acknowledgments

Unless otherwise mentioned, all research mentioned in the article was funded by the Department of Energy’s grants to their respective Energy Frontier Research Centers. Daniel DuBois’ early research on H2 electrocatalysis was conducted at the National Renewable Energy Laboratory and the University of Colorado. Wendy Shaw’s work was partly funded by the Early Career Research Program of the Department of Energy Office of Science. Stupp’s artificial muscle research also received funding from National Institutes of Health; National Science Foundation; Department of Homeland Security; Department of Defense; Paralyzed Veterans of America Research Foundation; and graduate, pre-doctoral, and post-doctoral fellowships from universities and other institutions; and non-EFRC Department of Energy awards. Many of these studies benefited from Department of Energy Office of Science user facilities and other experimental and computational resources.

About the author(s):

Ben Zhang is a third-year graduate student at Princeton University. His advisor, Gregory D. Scholes, is the Director of Bioinspired Light-Escalated Chemistry (BioLEC), an Energy Frontier Research Center funded by the Department of Energy. Ben’s work focuses on quantum mechanical interpretations of reaction dynamics probed by femtosecond spectroscopy.